Ruxolitinib Inhibits IFNγ Licensing of Human Bone Marrow Derived Mesenchymal Stromal Cells

Autor: Rafaela Scandolara, Charles Bruker, Keenan Hogan, Molly Mercedes Ryan, Ariel Joy Lipat, Jacques Galipeau, Mihir Patel, Rahul Das, Raghavan Chinnadurai
Rok vydání: 2021
Předmět:
Zdroj: Transplant Cell Ther
ISSN: 2666-6367
Popis: BACKGROUND: Ruxolitinib is a JAK2/JAK1 inhibitor which blocks inflammatory JAK-STAT signaling pathway. Ruxolitinib has been demonstrated to be effective in the treatment of steroid-resistant acute Graft vs Host Disease (GvHD). Ruxolitinib’s effect on inflammatory cells of hematopoietic origin is known. However, its effect on non-hematopoietic cell types with immune modulating and antigen presenting cell competency plausibly involved in pathogenesis of GvHD has not been explored. OBJECTIVE(S): Mesenchymal Stromal Cells (MSCs) are CD45(-) non-hematopoietic cells of the bone marrow with immune modulatory functions in vivo. MSC’s immunobiology largely depends on their responsiveness to IFNγ. We aimed to define the effect of Ruxolitinib on the immunobiology of MSCs that are modulated by IFNγ. STUDY DESIGN: Human bone marrow derived MSCs, peripheral blood mononuclear cells (PBMCs) and primary bone marrow aspirates were analyzed for their sensitivity to Ruxolitinib mediated blocking of IFNγ induced STAT-1 phosphorylation and downstream effector molecules, utilizing western blot, flow cytometry, secretome analysis and phosflow techniques. RESULTS: IFNγ induced cytostatic effects on MSCs are reversed by Ruxolitinib. Ruxolitinib inhibits IFNγ and secretome of activated peripheral PBMC induced STAT-1 phosphorylation on human bone marrow derived MSCs. In addition, Ruxolitinib inhibits IFNγ induced pro-GVHD pathways on MSCs which includes HLAABC(MHCI), HLADR(MHCII), CX3CL1 and CCL2. IFNγ induced immunosuppressive molecules IDO and PDL-1 were also inhibited by Ruxolitinib on MSCs. Comparative analysis with PBMCs has demonstrated that MSCs are as equal as to HLADR+ PBMCs populations in responding to Ruxolitinib mediated inhibition of IFNγ induced STAT-1 phosphorylation. Ex vivo analysis of human marrow aspirates has demonstrated that Ruxolitinib blocks IFNγ induced STAT-1 phosphorylation in CD45+/−HLADR+/− populations at different levels which is depending on their sensitivity to IFNγ responsiveness. CONCLUSION: These results inform the hypothesis that Ruxolitinib’s immune modulatory effects in vivo may pharmacologically involve marrow and tissue resident MSCs. Ruxolitinib affect the immunobiology of MSCs equivalent to professional HLADR+ APCs which collectively mitigate GvHD.
Databáze: OpenAIRE
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